ANG1005: PRELIMINARY CLINICAL SAFETY AND TOLERABILITY IN PATIENTS WITH RECURRENT MALIGNANT GLIOMA

Background: The blood–brain barrier (BBB) complicates the clinical treatment of most CNS diseases, including malignant glioma (MG). Angiopep-2 is a 19 amino acid peptide shown in animal models to cross the BBB using a physiological approach through transcytosis by binding to low-density lipoprotein receptor-related protein (LRP) expressed on the surface of the BBB. ANG1005 is a new chemical entity (NCE) that combines 1 molecule of Angiopep2 with 3 molecules of paclitaxel. Preclinical studies demonstrate the brain’s uptake of ANG1005 to be ~100x greater than paclitaxel and ~10x greater than temozolomide. Because LRP is upregulated on MG cells, once in the brain compartment, ANG1005 uses the same receptor-mediated mechanism described above to enter tumour cells where cleavage of ANG1005 occurs, releasing paclitaxel to perform its antimitotic functions. A Phase I clinical trial was initiated in October 2007 to explore the maximum tolerated dose (MTD) and obtain data on safety, tolerability and preliminary evidence of efficacy of ANG1005 in patients with recurrent MG. Material and methods: A multicenter, open-label, dose escalation study of ANG1005 is being conducted in the United States with sequential dose cohorts ranging from 30-558 mg/m 2 . ANG1005 is administered IV every 21 days. Study participants include adult patients with measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 who are ineligible for standard treatment options. Results: As of 06-Oct-2008, 14 patients with recurrent MG have received ANG1005 (8 patients with glioblastoma multiforme, 1 with anaplastic astrocytoma, and 5 with anaplastic oligodendroglioma). No patient has discontinued from the study due to study drug-related adverse events. Dose escalation is ongoing; the anticipated next cohort is 200 mg/m 2 . Conclusion: To date, treatment options for patients with recurrent MG are limited and prognosis is bleak because of the brain’s highly evolved physiological structure. Angiopep conjugates may provide a potentially safe and effective way to treat this and other currently unmanageable CNS diseases. ANG1005 is the first of a list of compounds to be tested in this regard.